JPS6133131A - Manufacture of thio, dithio or carbonyl group-containing organic compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention consists of reducing sulfonic acid chlorides, sulfoxides or halogeno derivatives of the general formula RA(II); This invention relates to a novel method for producing compounds. Several methods are known in the prior art for reducing sulfonic acid chlorides to disulfides. Benzenesulfonyl chloride can be converted to phenyl disulfide in ethereal solution by treating it with equimolar amounts of lithium aluminum hydride (J, Org, Chew, 1
951. (16), p. 946). 3-. Nitro-benzenesulfonic acid chloride is produced by hydrogenation method.
-Can be reduced to nitro-phenyl-disulfide (Or
g, 5ynth, Ca11. , Volume 5, (1973
)). Benzene sulfonic acid chloride can be converted to phenyl disulfide in an aqueous acetic acid solvent in the presence of red phosphorus and catalytic amounts of iodine (C, A, 52°2
791, (1958)). Sulfoxides can be reduced by, for example, a method using tin (n) chloride (Synthesis, 1973, p. 206).
, a method using hydrogen in the presence of a palladium/carbon catalyst (
Synthesis, 1975.385), a method using sodium borohydride in the presence of cobalt (If) chloride (J, Org, Chew, 19. (
46), p. 613) or a method using hydrogen iodide (
Z, Obs, Khim, 29.3033;C. A, 54.12096d). The methods described above have various drawbacks. That is, the yield is low;
lacks selectivity; is suitable only for the production of very specific compounds; requires extremely long reaction times to achieve sufficient yields; The condition class has disadvantages such as not being suitable for industrial large-scale production; The present inventors first discovered that the 5.5'-( The possibility of reduction to 2-carbomethoxyamino-benzimidazol)-yl-disulfide was investigated. The above two compounds are the excellent anthelmintic drug "Albendazol" (2-[(methoxycarbonyl)aminoco-5-propylthio-111-benzimidazole), published in German Patent Application No. 2.820, 3.
No. 75) is useful as an intermediate for production. The present invention provides a novel reduction method that is extremely suitable not only for the selective reduction of the sulfonic acid but also for the selective reduction of a large number of other compounds such as sulfonic acid chlorides, sulfoxides, and halogeno compounds. is provided. The novel reduction method of the present invention is applicable to the production of both new and known compounds. According to the invention, the general formula I R-X-R1 (1) [wherein X is thio, dithio or carbonyl; alkyl or 02-□2 alkenyl (which may optionally be hydroxy, carboxy, ct-e alkoxycarbonyl, amino, acetylamino, nitro, C1-6 alkylamino, C1-6 alkoxy, -CH2-C)I-1C, -7 cycloalkyl (possibly having one or more hydroxy groups) and/or one or more halogeno substituents);
C7-10 aralkyl; phenyl or naphthyl (which optionally has one or more Cl-4 alkyl, nitro, and/or halogeno substituents); 5-6 membered heterocyclic having 1 to 3 nitrogen atoms group, which is optionally fused to a benzene ring, and optionally
one or more identical or different substituents, preferably 2-
Carbomethoxyamino-IH-benzimidazole-5
-yl, pyrrolyl, indolyl, imidazolyl, benzimidazolyl, pyridyl, quinolyl, isoquinolyl, 1
゜2-11,3- or 1,4-diazonyl, 1゜2.
α-no)rogeno-substituted C7
-10aralkyl; or general formula -(CH2)n-Ha
represents a group u (in the formula, n is 1 to 6). ] In the method for producing a compound represented by the general formula (II), a compound represented by the general formula (II) (wherein A is chlorosulfonyl or the general formula is as defined above), (
b) A sulfur-containing sulfur compound that has an oxidation number of +4 and is converted to an oxidation number of +6 during a reduction reaction, or (b) A sulfur compound that is decomposed into a compound with an oxidation number of +4 in an acidic solvent. , preferably the amount of catalyst (however, the general formula ■
(0.5 mole or less per mole of starting material) of elemental iodine or a compound capable of releasing hydrogen iodide in an acidic solvent,
Alternatively, the sulfur compound used is reduced in an acidic solvent in the presence of a compound capable of being reduced to hydrogen iodide; and, if desired, the compound of general formula I thus obtained, in which R
is as defined above, and R1 represents hydrogen and X represents a dithio group, optionally in the presence of cyanide ions, to form a compound of the general formula R1-halogen (wherein R1 is C1-3 alkyl and halogen represents bromine or chlorine. The reaction is carried out at a temperature within the range of 10°C to 150°C, preferably 4°C.
It can be carried out at temperatures between 0 and 60°C. As a reaction solvent, an inert solvent or a mixture thereof, preferably water in an amount of 1 to 5
Mineral acids or organic acids containing 0% by weight or mixtures thereof can be used. Preferably, the organic solvent is acetic acid, formic acid or propionic acid, and the mineral acid is preferably sulfuric acid. Phosphoric acid or hydrochloric acid can be used. As the sulfur compound having an oxidation number of +4, sulfur dioxide, an alkali metal or alkaline earth metal sulfite, bisulfite or thiosulfate can preferably be used. As the compound that can be reduced to hydrogen iodide in an acidic solvent, preferably an alkali metal iodide can be used. The starting materials of the general formula (1) are partially known compounds. And it can be partially manufactured by a known method,
It is also commonly used in organic chemistry (J,
Chem, Soc, Co., 1981. (6)
. 295 pages). 2-Carbomethoxyamino-IH-benz. Some representative compounds among the compounds of the general formula (■) can be used as intermediates for the synthesis of Albendazol,
Other compounds also exhibit useful stimulant effects (West German Patent Publication Box 3,243,352). Among the compounds of the general formula (3) disclosed in the above-mentioned West German Patent Application Publication No. 2003-100000 and obtained by the method of the present invention, the following have particularly excellent properties. a) HO-(CH2)2-8-8-(CH2)2-
○H; b) HO-'(CH2)+-8-8-(CH
zh-OH;g) CHaO-(CH2)rS-5-
(GHz)z-OCH3k) CH30-CH2-C
(CHz)rS-5-C(CH3)2-CH2-○H=
) CHz-NH-(CH2)rS-8-(CH2)
2-NH-CH3n) 1-C3H7-8-8-(C
Hz) rOHo) t-C4Hg-8-8-(CH2
)2-OHOH q) 1-C3H7-5-5-CH2-CH-CH
3H r) t-C4Hg-3-8-CH2-CH-CH
:+t) 1-CaHrCH(i-C3H7)-8
-8-(CH2)2-OH The novel reduction method of the present invention has the following advantages. . According to the process of the invention, symmetrical and mixed thioethers and disulfides can be prepared from sulfides and sulfonic acids, respectively, and the halogen atoms adjacent to the altedohyde or ketocarbonyl groups can be replaced by halogens. The process of the invention is highly selective and can be carried out, for example, in the presence of alcoholic hydroxy groups, aldehyde-ketone or ester-carboxyl groups, carboxyl and nitro groups and optionally active double bonds. The present invention will be explained in more detail with reference to Examples below. The following examples are not intended to limit the scope of the invention. Preparation of L P-tolyl-disulfide 19 g (0.1 mol) of p-toluenesulfonyl chloride was dissolved in acetic acid Loom H, and then 1.5 g (0.01 mol) of sodium iodide was added. ,and,
The reaction mixture was stirred until the iodide was completely dissolved (5 minutes). The reaction mixture turned dark brown in color. A 30% aqueous sodium bisulfite solution was slowly added dropwise at such a rate that the iodide color of the reaction mixture disappeared upon addition. During the dropwise addition (approximately 30 minutes) the temperature of the reaction mixture rose to 60°C. The reaction was continued at this temperature until the iodide color disappeared. Upon completion of the reaction, the reaction mixture was diluted with 50 mQ of water and diluted with 20%
The pH value was adjusted to 4 by adding an aqueous sodium hydroxide solution. The reaction mixture was extracted three times with one 80 mQ portion of n-hexane. The hexane phases were combined, dried over anhydrous sodium sulfate, and evaporated at atmospheric pressure. Traces of solvent were removed from the distillation residue in vacuo at 70°C, and the product was crystallized at 20°C. 11.9 g of P-tolyl-disulfide were thus obtained. Yield 97%, m, p,: 43-45°C IH-NMR
: (CDCl2) : Aromatic 7.35 p
pm (d) 2H7,05ppm (d)
2H CH32, 8 ppm (s) 3H left J1 mochi y5 Production of phenyl disulfide The procedure of Example 1 was repeated except that benzenesulfonyl chloride was used as the starting material for p-)-riensulfonyl chloride. Thus, phenyl-
10 g of disulfide was obtained. Yield 93% 1m,p,: 58~b'H-NMR: (CDC13) Aromatic 7
．． 6-7.0 ppm (m) 1 bar

[Production of methyl disulfide] The procedure of Example 1 was repeated except that methanesulfonyl chloride was used instead of p-toluenesulfonyl chloride as the starting material. When purifying the reaction mixture, the pH value was adjusted to 8 instead of 4. The reaction mixture was also extracted three times with one 50 mQ portion of ether. The ether extracts were combined, dried and fractionated. 2.85 g of methyl disulfide were thus obtained. Yield 61%, b, p, :107-109℃ns=
1.5249 Example 4 Production of 5'-(2-carbomethoxyamino-benzimidazol)-yl-disulfide p as starting material
- 2-carbomethoxyamino-benzimidazole-5-sulfonyl chloride was used instead of toluenesulfonyl chloride, and when purifying the reaction mixture, extraction with hexane was omitted, and the reaction mixture was adjusted to pH 4. Example 1 was performed except that the crystals were filtered at 50° C. and the crystals were washed three times with one 10 m Q portion of warm water until free of sulfate ions. product to 10
Dry in vacuum at 0°C. Thus, the target compound is 1
8.2g was obtained. Yield 82%, m, p, : 323
~325°C 'H-NMR: (TFA-dt): C7-H7,
8ppm (s) 4HC6-87,6ppm
(s) '2HC4-H7,6ppm (s)
2HOCR34,0ppm (s) 3H Loss of Salmon Dan 2-[(methoxycarbonyl)-aminoco-5-propylthio-IH-benzimidazole Production of 5,5'-(2-carbomethoxyamino- 36 g of benzimidazole)-yl-disulfide, 30 g of potassium hydroxide, 25 mA of propyl bromide, 7 g of potassium cyanide, 250 mQ of water and 500 mA of acetone.
m 11. The reaction mixture was stirred at 20-25°C for 20 hours, then 35g of sodium bicarbonate was added. The precipitated product was filtered off and
voj 2% aqueous acetone 200m m and water 200m
Washed with Q. In this way, 3.3 g of the target compound was obtained. Yield 75%, n+, p: 210-212
Preparation of isolated p-tolyl-disulfide P-tolyl-cis-trans-1-propenyl-sulfoxide 10IIIQ was dissolved in 10 mΩ of acetic acid, and 0.2 g of sodium iodide was added. The temperature of the reaction mixture was
The reaction was started by raising to 0° C. and adding 2 drops of concentrated hydrochloric acid. The iodine produced is 30
% sodium bisulfite and after the iodine color disappeared, 3-5 drops of concentrated hydrochloric acid were added. When adding hydrochloric acid, concentrated hydrochloric acid and sodium bisulfite solution are added alternately until no iodine color is observed. The reaction mixture was diluted with 10 mΩ of water, the pH was adjusted to 8,
Then, the generated disulfide was extracted three times with one portion of n-hexane of 15 mΩ. After extraction, the hexane phases were combined, dried over sodium sulfate, and the solvent was removed. In this way, 2.1 g of P-tolyl-disulfide was obtained as a distillation residue. Yield 85%, m, p, : 43
~ 45℃ Loss of methyl-phenyl-thioether (thioanisole) instead of P-tolyl-cis-trans-1-propenyl-sulfoxide as a starting material.
Example 6 was carried out, except that sulfoxide was used and the distillation residue obtained after removal of the solvent was fractionated. In this way, 1.1 g of the target compound was obtained. Yield 88%, b, p: 181°C, n” = 1.5
850 (1 atm). ” H-NMR (CDCl2) Aromatic 7.8
ppm (s) 5H-CH37,6ppm
(s) Example 6 was carried out, except that n-propyl-p-tolyl-sulfoxide was used as the starting material for 3H production and the distillation residue obtained after removal of the solvent was fractionated. In this way, 1.4 g of the target compound was obtained. Yield 92%, b
, p, : 78-80 °C (266 Pa), n et al. 5=
1.5450 1H-NMR (CDC13) Aromatic 7.25
ppm (d) 2H7,05ppn+
(d) 2H 5C822,85ppm (t) 21(CH22
,3ppm (s) 38CH2C831,65p
pm (m) 2HCH2CH21.0ppm
(t) 3B to Group I Preparation of p-tolyl-allyl-thioether The procedure was as in Example 6, except that p-tolyl-allyl-sulfoxide was used as the starting material. In this way, 0.65 g of the target compound was obtained. Yield 39%, b, p,: 70-73°C (266P
a), n'' = 1.5710'H-NMR (CDCl2) Aromatic 7.25 p
pm (d) 2H7,05ppm (d)
2N-CH=6.1-5.6ppm (m) 3J,
(H,=CI(A=13Jco=CHB :cl(25,1ppm (dd) 21F
J(to H=CH5CH23,5ppm (d)
2H3J, (Hz, CH=6mF3'JCH2+=C
H2=0.8 -CH32,3ppm (s)' 38 cusp 11[
Preparation of History Phenyl-3-butenyl-thioether Example 6 was carried out as in Example 6, except that phenyl-3-butenyl-sulfoxide was used as the starting material. In this way, 1.2 g of the target compound was obtained. Yield 72% 'H-NMR (CDC13) Aromatic 7.5-7.
0 ppm (m) 5H-CH=6.15-5.
6ppm (IIl) IH=CH25,1ppm (
dd) 2H-5CH23,OPPm (t) 2H3
J (Hz, CH2=8-CH2CH22, 85ppm
(q) Preparation of p-tolyl-benzyl-thioether from 2H loss The procedure was as in Example 6, except that p-tolyl-benzyl-sulfoxide was used as the starting material. In this way, 1.9 g of the target compound was obtained. Yield 88.7%, m, p,: 43-44°C', H-
NMR (CDC13): Mono-substituted aromatic 7.25
ppm (s) 5H disubstituted aromatic 7.1
ppm (dd) 48-CH2-4,05p
pm (s) 2H-CHl 2.3 p
pm (s) 38 min. Preparation of phenyl-β-phenylethyl-thioether The procedure was as in Example 6, except that phenyl-β-phenylethyl sulfoxide was used as the starting material. In this way, 1.6 g of the target compound was obtained. Yield 75
%, n” = 1.6101”H-NMR (CDC1
;i) Aromatic 7.25-7.0 ppm,
(m) 10H-CH2CH2-3,0ppm
(m) Preparation of 4H "Ill"-n-propyl-5-(2-carbomethoxyamino-benzimidazol)-yl-thioether as in Example 6 except that sulfoxide was used. When purifying the reaction mixture, the hexane extraction was omitted, and the reaction mixture was neutralized to pH 7, and the precipitated crystals were filtered off and washed three times with one 10 mQ portion of water. Thus,
2.1 g of the target compound was obtained. Yield 79%, m, p,
: 210-212°C 1) 1-NMR (open SO):
-NH11,6ppm (s) LHC7-H',
7.45 ppm (s) LHC7-87, 35p
pm (d) 1BCs-H7,1ppm (d) I
H Q-CH33,75ppm (s) 3H5-C1(2
z, 7 sppm (t) 28-CH2CH31,55
ppm (m) 2H leaving m A- Production of phenylacetaldehyde α-bromo-α-phenyl-acetaldehyde 100 m
Q was dissolved in 100IIIQ acetic acid. In this solution,
0.3 g (2 mmol) of sodium iodide was added and the mixture was stirred until the iodide was completely dissolved. The iodine produced during the reaction was continuously reduced by adding 30% aqueous potassium bisulfite solution. (Bisulfite consumption: 4.5 mΩ.) Once no iodine was produced, the pH was adjusted to 4 by adding 10% aqueous sodium hydroxide solution. The reaction mixture was extracted with three portions of ether, 2-Omfl, the ether phases were combined, dried over sodium sulfate, and the ether was distilled off. The residue was fractionated in vacuo. Thus. 4.5g of the target compound was obtained. Yield 38%, b, p,
: 108°C (660Pa). 1H-NMR (CDCl2): CHO9, 75pPm
(t) IH aromatic 7.5-7.0 ppm (
lI+) 5H-CH2-3,65ppm (d)
2H'J, CH2CHO = = 2.3 Hz] 1''↓ As a starting material for the production of 1,000-p-nitro-acetophenone, promomethylphenylated ketone was used instead of α-bromo-α-phenylacetaldehyde. The same procedure as in Example 14 was carried out except for the above. The reaction mixture was purified not by the extraction method in Example 14, but by precipitating the product with 50 mfi of water, filtering off the precipitate, and washing it three times with one 20 mΩ portion of water. Thus, the target compound is 1
6.1g was obtained. Yield 98%, m, p, : 78-
79°C1H-NMR (CDC) 3) Aromatic
8.3 ppm (d) 2t (8.1ppm (
d) 2H -C832,6ppm (s) 3H 1E↓'-p-tolyl-5-(2-carbomethoxyamino-1[1
Preparation of -benzimidazole)-yl-disulfide 1.9 g (10 mmol) of P-toluene-sulfonyl chloride and 2.9 g (10 mmol) of 2-[(methoxycarbonyl)-amino]-IH-benzimidazole-5-sulfonyl chloride ( 10 mmol) was dissolved in 2On+Q acetic acid. Add 0.3 g of sodium iodide (2-
(mmol) was added and the mixture was stirred until the iodide was completely dissolved. The solution turned a dark iodine color. The iodine produced during the reaction was continuously reduced by adding 30% aqueous sodium bisulfite solution. The temperature of the reaction mixture slowly rose to 70°C within 30 minutes during the addition. At the end of the reaction, no iodine color was observed. The consumption of sodium bisulfite was 20 mQ. The p)l value of the reaction mixture was reduced to 4 by adding 20% aqueous sodium hydroxide solution.
Matched to. The precipitated crystals were filtered off and washed three times with one 20 mΩ portion of water. The product was converted into Kieselgel G (
Stahl) column (length, 25 cm; diameter, 2.5 c
m) under a pressure of 2 atm and diluted with a chloroform/acetic acid (9:1) mixture. The eluate whose Rf value of the target compound was 0.62 was evaporated to obtain the target compound. Yield 40%, m, P, ; 2
25-230℃

Claims (1)

[Claims] 1. General formula I R-X-R^1 (I) [wherein, X is thio, dithio or carbonyl; R and R^1 each independently represent hydrogen; chain or branched chain C_1_-_1_2 alkyl or C_
2_-_1_2 alkenyl {These may optionally be hydroxy, carboxy, C_1_-_6 alkoxycarbonyl, amino, acetylamino, nitro, C_1_-_
6 alkylamino, C_1_-_6 alkoxy, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, C_5_-_7 cycloalkyl (possibly has one or more hydroxy groups),
and/or has one or more halogeno substituents};
C_7_-_1_0 aralkyl; phenyl or naphthyl (which optionally has one or more C_1_-_4 alkyl, nitro, and/or halogeno substituents); 5- to 6-membered heterocyclic having 1 to 3 nitrogen atoms Group (
It is optionally fused to a benzene ring and also
Optionally one or more identical or different substituents, preferably 2-carbomethoxyamino-1H-benzimidazol-5-yl, pyrrolyl, indolyl, imidazolyl, benzimidazolyl, pyridyl, quinolyl, isoquinolyl, 1,2- , 1,3- or 1,4-diazonyl, 1,2,4- or 1,3,5-triazinyl, phthalazinyl or quinoxanyl);
(CH_2)_n-Hal (in the formula, n is 1 to 6)
Indicates the group of ] In the manufacturing method of the compound represented by the general formula II R-A (II) (where A is chlorosulfonyl or the general formula ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ group; R^1 and R are as defined above. sulfur-containing sulfur compounds that are converted to
b) A sulfur compound that is decomposed into a compound with an oxidation number of +4 in an acidic solvent, preferably a catalytic amount (however, not more than 0.5 mol per mol of the starting material of general formula II) of elemental iodine or an acidic solvent. in the presence of a compound capable of liberating hydrogen iodide in an acidic solvent or a compound capable of reducing hydrogen iodide to hydrogen iodide in an acidic solvent with the sulfur compound used; Compound (wherein, R
is as defined above, and R^1
represents hydrogen and X represents a dithio group), optionally in the presence of cyanide ions, with the general formula R^1-halogen (wherein R^1 is C_1_-_3 alkyl,
And halogen indicates bromine or chlorine. ) of the general formula I by alkylation by known methods.
A method for producing a compound. 2. General formula I R-X-R^1 (I) {In the formula, R is an aromatic group (this group may be C_1_
-_4 alkyl, nitro, amino, C_1_-_4 alkylamino, acylamino, C_2_-_4 alkoxycarbonylamino, C_1_-_4 acyl and/or halogeno substituents), or C_1_
-_1_2 alkyl group (this group may be hydroxy,
substituted with carboxy, C_2_-_4 alkoxycarbonyl, amino, acetylamino or nitro group; X represents a thio or dithio group; and R^1 represents hydrogen, hydroxy or a C_1_-_6 acyl group }, wherein a compound represented by the general formula II RA(II) (wherein A is a chlorosulfonyl group and R is as defined above) is reduced with an iodine compound and a sulfur compound of oxidation number +4 or a sulfur compound decomposed to that of oxidation number +4 in an acidic solvent, and, if desired, the compound thus obtained is reduced, optionally in the presence of cyanide. A method for producing a compound of the general formula I, comprising alkylating or acylating the compound as follows. 3. The manufacturing method according to claim 1 or 2, wherein the reduction is carried out in a mixture of water and a mineral acid and/or an organic acid. 4. In the manufacturing method according to claim 3,
The above-mentioned manufacturing method comprises using sulfuric acid or hydrochloric acid as the mineral acid and acetic acid as the organic acid. 5. The manufacturing method according to claim 1 or 2, which comprises using an alkali metal bisulfite, sulfite or thiosulfate as the compound with an oxidation number of +4. 6. In the production method according to claim 1 or 2, an alkali metal iodide, preferably sodium iodide, is used as the compound that releases hydrogen iodide in an acidic solvent. The manufacturing method. 7. In the production method according to claim 1 or 2, elemental iodine or a compound releasing hydrogen iodide in an acidic solvent is added in an amount of 0.05 to 1 mole of the starting material of general formula II. Said manufacturing method, comprising using an amount of 0.1 mol. 8. The manufacturing method according to claim 1 or 2, wherein the reduction is carried out at a temperature of 10 to 150°C, preferably 40 to 120°C. 9. Compounds of general formula I (wherein R, X and R^1 are as defined in claim 1,
Further, R and R^1 are mutually different groups. )